Differential Effect of Mucosal NKp44+ Innate Lymphoid Cells and Δγ Cells on Simian Immunodeficiency Virus Infection Outcome in Rhesus Macaques

Abstract

NK cells are essential for controlling viral infections. We investigated NK cell and innate lymphoid cell (ILC) dynamics and function in rhesus macaque rectal tissue and blood following mucosal priming with replicating adenovirus (Ad)-SIV recombinants, systemic boosting with SIV envelope protein, and subsequent repeated low-dose intravaginal SIV exposures. Mucosal memory-like NK and ILC subsets in rectal and vaginal tissues of chronically infected macaques were also evaluated. No differences in NK cell or ILC frequencies or cytokine production were seen between vaccinated and Ad-empty/alum controls, suggesting responses were due to the Ad-vector and alum vaccine components. Mucosal NKp44 + ILCs increased postvaccination and returned to prelevels postinfection. The vaccine regimen induced mucosal SIV-specific Ab, which mediated Ab-dependent cellular cytotoxicity and was correlated with mucosal NKp44 + CD16 + ILCs. Postvaccination NKp44 + and NKp44 + IL-17 + ILC frequencies were associated with delayed SIV acquisition and decreased viremia. In chronically SIV-infected animals, NKp44 + ILCs negatively correlated with viral load, further suggesting a protective effect, whereas, NKG2A 2 NKp44 2 double-negative ILCs positively correlated with viral load, indicating a pathogenic role. No such associations of circulating NK cells were seen. Dg NK cells in mucosal tissues of chronically infected animals exhibited impaired cytokine production compared with non-Dg NK cells but responded to anti-gp120 Ab and Gag peptides, whereas non-Dg NK cells did not. Mucosal Dg NKp44 + and Dg DN cells were similarly associated with protection and disease progression, respectively. Thus, the data suggest NKp44 + ILCs and Dg cells contribute to SIV infection outcomes. Vaccines that promote mucosal NKp44 + and suppress double-negative ILCs are likely desirable.

The Immunological Impact of Adenovirus Early Genes on Vaccine-Induced Responses in Mice and Nonhuman Primates

“…(38). Thus, to determine if the E4 genes had any impact on this ability we performed ADCC as summarized in the method section and described elsewhere (52). Here, even though the ADCC values from the ΔE4 Ad-immunized NHPs were higher than those of the other Ad-immunized NHPs, no significant differences were observed either against gp120 or rhFLSC targets ( Fig 5C).…”

“…ADCC activity was assessed as previously described using EGFP-CEMNKr-CCR5-SNAP cells that constitutively express GFP as targets (52). Briefly, one million target cells were incubated with 50 μg of BAL gp120 or rhFLSC recombinant protein for 2 h at 37ºC, washed, and labeled with SNAP-Surface Alexa Fluor 647 (New England Biolabs, Ipswich, MA; cat.# S9136S) as on March 21, 2021 by guest http://jvi.asm.org/ Downloaded from recommended by the manufacturer for 30 min at RT.…”

Innate Lymphoid Cells Activation and Transcriptomic Changes in Response to Human Dengue Infection

“…Helper ILCs are classified into ILC1, ILC2, and ILC3, based on expression of major transcription factors and their signature cytokines, which resemble those of Th1, Th2 and Th17/Th22 cell subsets. In general, ILC1 produces IFN-γ; ILC2 produces IL-4, IL-5 and IL-13; and ILC3 produces IL-17A and/or IL-22 ( 32 , 33 , 36 , 37 ). Recent evidence also showed the plasticity of ILCs that enable them to promptly respond to environmental changes ( 38 ).…”

Type 3 Innate Lymphoid Cells as Regulators of the Host-Pathogen Interaction

“…The aforementioned study corroborated the premise that the lentivirus infection could have significant effects on the frequency, phenotype, and function of innate cells in the oral and gut mucosa such as the reduction of ILC3 IL-22 + which might be particularly relevant in infants infected through breastfeeding, because their immune system is not fully functional (62). Importantly, it has recently been demonstrated that NKp44 + ILCs play a protective role in the progression of the disease, as their higher frequency in the mucosa was associated with delayed SIV acquisition and decreased viremia in vaccinated macaques (63), thus confirming previous published data (64).…”